The present invention relates to moderately soluble benzene sulfonic acid salts of pramipexole and their use in pharmaceutical compositions and treatments.
Pramipexole, or 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, is a known pharmaceutically active agent that has been proposed for treating schizophrenia, Parkinson's disease or Parkinsonism, and/or hypertension (see for example U.S. Pat. No. 4,843,086 and EP 186087). The commercial form of pramipexole has been the dihydrochloride salt of the (S)-enantiomer thereof. The dihydrochloride salt compound is very soluble in water and it is hygroscopic. In solid state, it is generally isolated as a crystalline monohydrate and, indeed, the commercially marketed tablets contain pramipexole dihydrochloride monohydrate. EP 186087 generically teaches the formation of acid addition salts of pramipexole and other similar tetrahydrobenzothiazoles, but only the dihydrochloride salts are exemplified.
Published U.S. patent application No. US 2002-0103240 discloses, inter alia, a process for resolving pramipexole. The process can involve the use of a monobasic salt form of pramipexole as a starting material or intermediate. The monobasic salts, unlike the dihydrochloride salts of EP 186087, have only one acid moiety for each pramipexole. Acids suitable for forming a monobasic salt of pramipexole include hydrochloric, hydrobromic, acetic, benzoic, methane sulfonic, ethane sulfonic, trifluoromethane sulfonic, benzene sulfonic and p-toluene sulfonic acids. Specific examples of monobasic salts include pramipexole monohydrochloride, pramipexole monohydrobromide, pramipexole methanesulfonate, pramipexole trifluoromethanesulfonate, pramipexole p-toluenesulfonate, and pramipexole benzoate. The monobasic salts are primarily taught to be reacted with an optically active acid to form a so-called “mixed salt,” which in turn facilitates resolution of the (R) and (S) enantiomers via preferential precipitation.
It would be desirable to have a pharmaceutically acceptable pramipexole salt with more moderate water solubility and/or lower hygroscopicity than the known pramipexole dihydrochloride. Such a salt could provide for better storage stability and/or handling. It would further be desirable to form pramipexole compositions from such a salt. Such formulations may avoid the present need that tablets comprising highly soluble pramipexole salt must,be administered three times a day.